Back ground: Histogenesis and organogenesis is believed to be directed by programmed cell-cell and cell-to-matrix interactions. Cell-cell adhesiveness is determined by specific cell adhesion molecules (CAMs), whose modular expression is also thought to regnlate cell proliferation and/or differentiation. An important feature of CAMs is their developmentally regulated expression which appears to play important roles during histogenesis and organogenesis of various tissues including the pancreas. Their cell type-specific expression may therefore be used to identify cell populations at defined stages of development. Furthermore, CAMs are required for the maintenance of tissue architecture, which in turn is critical to organs' function. In fact, we have previously demonstrated that adhesion molecules such as NCAM are involved in the maintenance of the three-dimensional organization of pancreatic islet cells, with insulin-secreting a-cells located in the core, and the other endocrine cell types ((x, 8, and pp, secreting glucagon, somatostatin and pancreatic polypeptide, respectively) arranged at the periphery. This peculiar islet cell type segregation is perturbed in diabetes suggesting that such a configuration might be necessary for proper islet function. Objectives: Our current efforts focus on the identification and functional characterization of CAMs involved in the ontogeny of human pancreatic islets. Summarv of the past vear achievements: Experiments were designed to identify cell-cell adhesion molecules (CAMs) expressed by fetal pancreatic cells, and to understand their functional role in cell-cell adhesion, proliferation, and endocrine differentiation. In particular, we have identified EpCAM as a major mediator of pancreatic epithelial cell-cell adhesion. Interestingly, this CAM appeared to be involved in epithelial cell growth. Part of this work entailed use of the confocal microscope and the IvEM at the NCMIR. These data are the subject of a manuscript in preparation (Cirulli et al., 1996). In addition, based on our previous experience suggesting an important role of mesenchyme-derived growth factors such as HGF/SF in proliferation of human fetal pancreatic cells, we have examined the expression pattern of the C-MET receptor for HGF/SF within the human pancreas both in fetal and adult life. These eperiments have determined that C-MET is restricted to the epithelial compartment of the developing human pancreas, and that it becomes predominantly expressed on endocrine cells (islets of Langerhans) in the adult pancreas (Otonkoski et al., 1996). Finally, our search for markers of endocrine differentiation led to the identification of GAD65 (Glutamic Acid Decarboxylase, 65kD) within epithelial cells entering the pathway of endocrine differentiatrion (i.e. insulin and/or glucagon expression). These study has also been recently accepted for publication (Mally et al., 1996).